Endocrine Abstracts

Thyroid hormones (TH) synthesis requires iodine, a scarce element whose recycling is mediated by the iodotyrosine dehalogenase (encoded by the DEHAL1 gene) through deiodination of mono- and di-iodotyrosines. In humans, biallelic mutations in DEHAL1 lead to a severe form of congenital hypothyroidism (CH) non detectable by neonatal screening programs, which involves the risk of mental retardation. The timing and triggering factors of this particular type of hypothyroidism remain unknown and may require iodine storage depletion. Our aim was to study the amount of iodinated metabolites and TH profile in newly generated Dehal1 knockout mice under controlled iodine diets. Heterozygus (Dehal1^+/−), homozygous (Dehal1^−/−) and Wildtype (WT) mice were fed during 4 weeks with pellets containing very low iodine amounts. Additionally, the drinking water was iodine enriched leading to three experimental groups: sufficient, non-sufficient and deficient iodine treated mice (7.0, 1.2 and 0.2 μg/day, respectively; 4 months old mice, n=6 per treatment and genotype,). At the beginning (d0) and the end (d28) of the experiment, urine iodine concentration (UIC; respect to creatinine) and serum total T₄ and T₃ were determined by the Kolthof-modified method and radioimmunoassays, respectively. The status of Dehal1 gene in knockout mice were validated via genotyping (mouse tail DNA PCR), vector gene reporter staining (X-gal for β-galactosidase activity) and tissue specific protein expression (western blot and immunohistochemistry). At d0, UIC were significantly increased (P < 0.05) in both Dehal1^+/− and Dehal1^−/− (on average, 2.8±1.0 μg/ml) compared to WT mice (1.1±0.6 μg/ml), while T₄ and T₃ were similar between groups (on average, 62.4±5 and 0.63±0.1 ng/ml, respectively). At d28, in mice undergoing iodine sufficient and deficient treatments, UIC and TH levels were similar between groups. Remarkably, under non-sufficient iodine conditions TH levels were lower in Dehal1^+/− and Dehal1^−/− compared to WT mice (P < 0.05). Our data show that an increased loss of iodine in urine anticipates a hypothyroidism in Dehal1 deficient mice which is triggered by a non-sufficient iodine intake. Therefore, iodinated metabolites may provide new opportunities for early detection of Dehal1 deficiency preventing mental alterations related to late diagnosed CH.